The long-term goal of the proposed research is the development of improved chemotherapy and/or radiation therapy treatment strategies for mismatch repair deficient cancers based on a comprehensive modeling and systems and control framework using a systems biology approach. As a first step in achieving this long-term goal, the proposed research is directed at developing synergistic experimental and computational frameworks that will enable the study of the cellular and molecular aspects of mismatch repair. The experimental data and models developed in this work will provide the necessary foundation for the subsequent efforts directed at the development of improved treatment strategies for resistant (damage tolerant) cancers. A stochastic hybrid model for the mismatch repair process will be developed using data from mismatch repair reconstitution experiments with purified proteins. The model will capture the basic dynamics of the biochemical mechanisms governing the mismatch repair pathway, and in silico experiments with the model will be used to improve the understanding of the mismatch repair process and to generate further hypotheses that can be tested experimentally. The model will then be modified using the data from these cellular experiments. The mismatch repair pathway will be reconstituted in vitro using purified proteins to obtain kinetic parameter estimates for the computational model from measurements on protein activity. A cellular experimental model, consisting of genetically manipulated MMR+ versus MMR- cells, will be used to test and further validate the computational model with respect to treatment responses. PUBLIC HEALTH RELEVANCE: One of the DNA repair mechanisms will be studied both experimentally and computationally to improve the understanding of the repair process dynamics under treatment conditions. A detailed understanding of these treatment responses using computational models will provide valuable therapeutic information in the treatment of drug resistant cancers.